H. G. Pars Pharmaceutical Laboratories' long-term goal is to develop and market an orally active antihypertensive drug from its series of sulfur and nitrogen cannabinoid analogs. Hypotensive cannabinoids are believed to exert their effects by altering central sympathetic nervous system activity but the exact mechanism of action is not known and may differ from that of antihypertensive agents on the market. Preliminary cardiovascular/behavioral data indicates that four PARS' compounds (SP-119, SP-269, 273 and 276) show a favorable separation of blood pressure lowering activity and adverse side effects. Hypotensive activity in conscious and anesthetized spontaneous hypertensive (SH) and normotensive rats was of long duration and comparable in magnitude to that of Clonidine. During Phase I we will resynthesize the four analogs and perform more extensive evaluations of their antihypertensive activity in SH rats and behavorial effects in mice. The candidate with the best therapeutic ratio, SP-X, will undergo further evaluation in a 20 day repeat dose study. Results will be compared with clonidine data. Successful completion of this project will allow application for Phase II funds for preparing an oral formulation of SP-X, performing pre-clinical studies and conducting early safety and efficacy trials in human subjects.